title: BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency: molecular requisites for the mitochondrial pathway to apoptosis in platelets.
abstract: A pivotal step in the mitochondrial pathway of apoptosis is activation of Bak and Bax, although the molecular mechanism remains controversial. To examine whether mitochondrial apoptosis can be induced by just a lack of antiapoptotic Bcl-2-like proteins or requires direct activators of the BH3-only proteins including Bid and Bim, we studied the molecular requisites for platelet apoptosis induced by Bcl-xL deficiency. Severe thrombocytopenia induced by thrombocyte-specific Bcl-xL knock-out was fully rescued in a Bak and Bax double knock-out background but not with single knock-out of either one. In sharp contrast, deficiency of either Bid, Bim, or both did not alleviate thrombocytopenia in Bcl-xL knock-out mice. An in vitro study revealed that ABT-737, a Bad mimetic, induced platelet apoptosis in association with a conformational change of the amino terminus, translocation from the cytosol to mitochondria, and homo-oligomerization of Bax. ABT-737-induced Bax activation and apoptosis were also observed in Bid/Bim-deficient platelets. Human platelets, upon storage, underwent spontaneous apoptosis with a gradual decline of Bcl-xL expression despite a decrease in Bid and Bim expression. Apoptosis was attenuated in Bak/Bax-deficient or Bcl-xL-overexpressing platelets but not in Bid/Bim-deficient platelets upon storage. In conclusion, platelet lifespan is regulated by a fine balance between anti- and proapoptotic multidomain Bcl-2 family proteins. Despite residing in platelets, BH3-only activator proteins Bid and Bim are dispensable for Bax activation and mitochondrial apoptosis.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D021381:Protein Transport; D013449:Sulfonamides / Q000494:pharmacology; D013921:Thrombocytopenia / Q000188:drug therapy; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*; D051020:bcl-X Protein / Q000172:deficiency*
chemical_list: C501332:ABT-737; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein